Coordinated cardiac contractility is governed by electrical changes that occur in cardiomyocytes. The cardiac impulse or action potential is determined by successive opening and closing of membrane ion channels that regulate the depolarizing (mainly Na+ and Ca++) and repolarizing (mainly K+) currents (Nerbonne and Kass, 2005). Genetic defects resulting in the malfunctioning of these channels and the associated ionic currents can lead to cardiac rhythm disorders generally described as cardiac channelopathies (Webster and Berul, 2013). Inherited mutations in cardiac ion channels resulting in gain or loss of channel function can alter the atrial and ventricular action potential and cause various cardiac arrhythmia syndromes, including long QT syndrome (LQTS), short QT syndrome, Brugada syndrome, and familial atrial fibrillation (Giudicessi and Ackerman, 2012). Prolongation of QT interval caused by abnormal cardiac repolarization is associated with an increased risk of life-threatening tachyarrhythmia. Presently 16 genes associated with LQTS have been identified with differing signs and symptoms, depending on the locus involved. The majority of cases have mutations in the KCNQ1 (LQT1), KCNH2 (LQT2) and SCN5A (LQT3) genes (Schwartz et al. 2013).
Cardiac repolarization is primarily mediated by the slow delayed rectifier current, IKs (KCNQ1) and the rapid delayed rectifier current IKr (KCNH2) conducted by the hERG channels (Sanguinetti and Tristani-Firouzi, 2006). Impairment or loss of K+ channel function delays cardiac repolarization, leads to excessive prolongation of the action potential duration and associated QT interval in the electrocardiogram and predisposes affected individuals to high risk of developing torsades de pointes arrhythmia and sudden cardiac death (Ravens and Cerbai, 2008). Jervell and Lange-Nielsen syndrome (JLN) is a rare cause of LQTS characterized by deafness, severe QT prolongation and lethal arrhythmias (Crotti et al. 2008). Most patients die of this disorder as children before age 10 despite aggressive therapy including behavior modification, beta blockers, defibrillators and sympathectomy. This syndrome is caused by homozygous or compound heterozygous mutations in genes KCNQ1 and KCNE1 that are responsible for the delayed rectifier repolarizing current IKs (Crotti et al. 2008). Acquired LQTS is often observed in the setting of structural or functional cardiac disease such as ischemic or diabetic cardiomyopathy. The altered substrate in coronary disease (ischemia or scar) may lower the threshold for afterdepolarization. Thus, subclinical IKs dysfunction with associated reduction in repolarization reserve may be exacerbated in these conditions.
hERG channel activators described in the literature include NS1643, NS3623, RPR260243, PD-118057, PD307243, ICA105574, A935142 and KB130015 (Zhou et al., 2011). These compounds act by altering channel activation, inactivation or deactivation (Perry et al. 2010). Pharmacological activation of hERG K+ channels is anticipated to normalize the QT interval, functionally mitigate the arrhythmic substrate and consequently reduce cardiac arrhythmia in patients with inherited or acquired LQTS. This approach is likely to be effective in LQTS resulting from mutations in genes other than KCNQ1 since it targets the alteration in QT per se and not specific genetic defects. hERG channel activators may also function as general antiarrhythmics since they reportedly reduce electrical heterogeneity in the myocardium and thereby reduce the possibility of re-entry (Grunnet et al. 2008). Thus, the current invention relates to hERG activators useful as pharmaceuticals for the treatment of genetic or acquired long QT syndromes and as a novel class of agents for the treatment of arrhythmias of other etiologies.    1. Nerbonne J M, Kass R S. Molecular physiology of cardiac repolarization. Physiol Rev. 2005; 85:1205-53.    2. Webster G, Berul C I. An update on channelopathies: from mechanisms to management. Circulation. 2013; 127:126-40.    3. Giudicessi, J. R. & Ackerman, M. J. Potassium-channel mutations and cardiac arrhythmias—diagnosis and therapy. Nat Rev Cardiol. 2012; 9:319-32.    4. Schwartz P J, Ackerman M J, George A L Jr, Wilde A A. Impact of Genetics on the Clinical Management of Channelopathies. J Am Coll Cardiol. 2013 May 15 (Epub ahead of print)    5. Sanguinetti M C, Tristani-Firouzi M. hERG potassium channels and cardiac arrhythmia. Nature. 2006; 440:463-9.    6. Ravens U, Cerbai E. Role of potassium currents in cardiac arrhythmias. Europace. 2008; 10:1133-7.    7. Crotti L, Celano G, Dagradi F, Schwartz P J. Congenital long QT syndrome. Orphanet J Rare Dis. 2008; 3:18.    8. Zhou P Z, Babcock J, Liu L Q, Li M, Gao Z B. Activation of human ether-a-go-go related gene (hERG) potassium channels by small molecules. Acta Pharmacol Sin. 2011; 32:781-8.    9. Perry M, Sanguinetti M, Mitcheson J. Revealing the structural basis of action of hERG potassium channel activators and blockers. J Physiol. 2010; 588(Pt 17):3157-67.    10. Grunnet M, Hansen R S, Olesen S P. hERG1 channel activators: a new anti-arrhythmic principle. Prog Biophys Mol Biol. 2008; 98:347-62.